This invention relates to the process of lyophilization, also called freeze drying, of pharmaceutical drugs and biologicals.
Generally, lyophilization, or freeze drying, is a process that extracts water from a compound so that the compound remains stable and can be stored at ambient air temperature. In the pharmaceutical industry, it is known to freeze dry drugs and biologicals to maintain the stability of these drugs and biologicals at room temperature over a long period of time. In the manufacture of pharmaceutical drugs and biologicals, the freeze drying process usually takes place in vials in a freeze drying chamber. Hundreds or thousands of vials can be freeze dried at the same time in a production run in a freeze drying chamber that can be refrigerator size or even room size. One example of a freeze drying chamber for holding many vials is shown in U.S. Pat. No. 5,421,686.
Low temperature is applied to the vials to freeze the moisture (or other solvents) in the drugs or biologicals to produce ice, and then low pressure is applied to effect sublimation of the ice; that is, the ice passes from a solid phase directly to a gas phase without an intermediate liquid phase. This is referred to as the primary drying stage. The gas is then exhausted from the chamber.
As the sublimation of the ice proceeds, a dried product layer (referred to as a xe2x80x9ccakexe2x80x9d) is produced above the ice. This product resists the diffusion of moisture generated from the ice beneath it during freeze drying. This resistance (referred to here as xe2x80x9ccake resistancexe2x80x9d) can be a useful parameter to know for optimizing the freeze drying process. A high cake resistance can slow manufacturing significantly, and may even cause product collapse. Efficiency is important because the process is time-consuming and it is desirable to run the manufacturing equipment at all times if possible.
Two methods have been proposed to determine the cake resistance. In a microbalance method, cake resistance is measured during freeze-drying in a specialized microbalance. Pikal et al., xe2x80x9cPhysical Chemistry of Freeze-drying: Measurement of Sublimation Rates for Frozen Aqueous Solutions by a Microbalance Technique,xe2x80x9d Journal of Pharmaceutical Sciences, 72 (1985) 635-650. The microbalance is shown in FIG. 2 of the article. The method described in Pikal et al. is not necessarily accurate for a production sample, however, because there are differences between the conditions in the microbalance and those in the manufactured products in a production run.
In another method, cake resistance is estimated using an indirect method which calculates the resistance as a parameter in a mathematical model. Milton et al., xe2x80x9cEvaluation of Mamometric Temperature Measurement as a Method of Monitoring Product Temperature During Lyophilization,xe2x80x9d PDA Journal of Pharmaceutical Science and Technology, 51(1997), 7-16. Since the resistance is not determined directly in this case, the result may not be reliable for optimizing the freeze drying process.
It is a continuing goal in pharmaceutical manufacturing to improve the efficiency of the lyophilization process.
The present invention includes a system and method for measuring cake resistance in a production sample of a product during or after the freeze drying process. The results of the cake resistance measurement can be used to change the freeze drying parameters, such as temperature and/or pressure, to optimize the process to reduce this cake resistance in future processes, and/or to change the composition that is being freeze dried in future processes. By introducing a gas with a controlled pressure or flow (volume per unit of time), it is possible to determine cake resistance by measuring a resulting gas flow or pressure, respectively, from one of a number of production products.
In another aspect, the invention includes a freeze drying system and method with a cake resistance measuring system and feedback for controlling parameters of the freeze drying process during processing. This allows the system to monitor the resistance and alter the temperature and/or pressure during the processing.
In yet another aspect, the invention includes a freeze drying system and method whereby cake resistance is measured through the application of a controlled flow or pressure of gas through multiple tubes to multiple samples. The tubes are located at different depths in the products being measured. By measuring the cake resistance with tubes at different depths into the products being freeze dried, a useful understanding about the manufacturing process can be obtained and used to control the parameters of the freeze drying process in real time or for subsequent processing. The measurements can be taken during or after freeze drying.
This device permits one to determine the cake resistance of a freeze dried product directly from a production sample while the freeze drying is taking place or soon thereafter, rather than in a specialized device or through an indirect estimation method, and to use the results to monitor and preferably improve the freeze drying process in real time or subsequently. Such an improvement is useful and important in large scale freeze drying where equipment is used as continuously as possible. Other features and advantages will become apparent from the following detailed descriptions, drawings, and claims.